The long-term goal of this research program is to understand of the roles of coagulation and fibrinolytic factors in hemostasis, wound repair, inflammatory response, and disease pathobiology. The recent generation of viable mouse lines with selected deficits in key hemostatic factors has provided a unique opportunity to rigorously define the roles of specific factors in both physiological and disease processes. The primary objective of this research proposal is to exploit this opportunity to directly establish the importance and mechanistic role of hemostatic factors in bacterial virulence and host inflammatory response. The focus of these studies will be the bacterial pathogens, Y. pestis and S. aureus, two microorganisms that express well-described bacterial plasminogen activators, procoagulants, and fibrin(ogen) binding proteins. The project aims center on the following specific hypotheses: i) host coagulation and fibrinolytic factors are critical in bacterial virulence and pathogenesis, ii) fibrin(ogen) and plasmin(ogen) have a fundamental role in mediating host inflammatory response at sites of infection, iii) fibrin(ogen) alters inflammatory cell activity at sites of infection through the engagement of the integrin, CD11b/CD18, and iv) hemostatic factors play an important role in the inflammatory response, regardless of the challenge or tissue. These hypotheses will be tested though detailed studies of Y. pestis and S. aureus infection and host inflammatory response in mice with specific deficits in plasminogen activator, plasminogen, and fibrinogen (Specific Aims 1 and 2). The mechanistic role of fibrin(ogen)-integrin interaction in the inflammatory response will be explored by comparative studies of infection and inflammation in mice expressing mutant forms of fibrinogen lacking the motifs recognized by the platelet integrin, alphaIIbbeta3, and the leukocyte integrin, CD11b/CD18 (Specific Aims 2 and 3). Finally, the role of fibrin(ogen) in inflammatory processes unrelated to bacterial infection will be explored by studying the impact of fibrinogen deficiency on leukocyte emigration, adhesion, and function, using peritonitis and dermatitis model systems (Specific Aim 4). The proposed studies will provide a more detailed understanding of the role of coagulation/fibrinolytic factors in bacterial pathogenesis and the inflammatory response, and could ultimately lead to the development of new therapeutic strategies for the treatment of both bacterial infection and inflammatory diseases.